The Program is directed at structural studies of macromolecules, a macromolecular assemblies, and cell organelles such as ribosomes and plasma membranes. The major techniques to be employed center on X-ray diffraction from single crystals or from solutions or partially ordered systems; on high resolution solution NMR; on a whole range of other biophysical techniques, including mass spectroscopy, either by themselves or in combination with chemical labeling procedures. In addition to the time-average structures, which are the most immediate output of the diffraction work, the Program will be especially aimed at studying the relative motion of various parts (domains) of the polymer chains and of the subunits with respect to each other in the larger aggregates. Motion can, in part, be inferred from different static structures that can be determined under varied conditions of environment and ligation. Of special interest is the motion during: 1) the catalytic cycles of polymerases along their nucleic acid templates and substrates; 2) the rearrangement of protein subunits during the ligand-regulated formation of specific protein/DNA complexes and of the complexes themselves during DNA recombination; 3) the movement of ribosomes on the message during the translocation step of protein synthesis; and 4) the secretion of polypeptide chains into and through the membrane bilayer. The theoretical approaches will include free-energy perturbation calculations on various systems, modeling of protein-DNA and protein-membrane interactions, modeling the macromolecule-solvent interface, and continuing improvement of the structure refinement procedures for both X-ray and NMR data.